Thymic B cells and T cell selection

胸腺 B 细胞和 T 细胞选择

• 批准号: 8605827
• 负责人: Haochu Huang
• 金额: $ 41.09万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605827
• 关键词: Address; Affect; Affinity; Alleles; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Arthritis; Autoantigens; Autoimmune Diseases; B cell repertoire; B-Lymphocytes; Bone Marrow; Cells; Chimera organism; Dendritic Cells; Development; Disease; Experimental Models; Glucosephosphate Isomerase; High Prevalence; Individual; K/BxN model; Light; MHC Class II Genes; Mediating; Mixed Lymphocyte Culture Test; Modeling; Mus; Pathway interactions; Peptides; Peripheral; Population; Process; Receptors, Antigen, B-Cell; Rheumatoid Arthritis; Role; Shapes; Specificity; Superantigens; System; T-Cell Immunologic Specificity; T-Cell Receptor; T-Lymphocyte; Thymus Gland; Time; Transgenes; antigen binding; autoreactive T cell; base; central tolerance; defined contribution; in vitro Assay; in vivo; insight; macrophage; mouse model; neglect; novel; prevent; public health relevance; purge; research study; thymocyte; uptake

DESCRIPTION (provided by applicant): Negative selection is the major mechanism of central tolerance by which autoreactive T cells are purged from the repertoire. This process depends upon presentation of self-peptides to developing thymocytes by antigen-presenting cells (APCs). Although the question of which APC is responsible for negative selection has been investigated extensively, the role of thymic B cells as APCs in negative selection has been largely neglected. Among bone marrow-derived APCs, which include dendritic cells (DCs), B cells and macrophages, DCs are ascribed to mediate negative selection based on in vitro assays that compare the efficiency of antigen presentation by these different cell populations. Nevertheless, while B cells are poor at presenting antigens via non-specific uptake, they can present antigens that bind to their B cell receptors (BCR) with even higher efficiency than DCs. Our preliminary studies indicate that antigen-specific thymic B cells are excellent APCs for T cell negative selection. Although the presence of B cells in the thymus has been recognized for several decades, their function is not well understood. They are concentrated in the medulla and cortical-medullary junction along with DCs and express high levels of MHC class II. The capacity of thymic B cells to delete thymocytes has been demonstrated in a superantigen model. It remains unclear whether they can mediate negative selection for cognate antigens recognized by BCRs and what their influence on the T cell repertoire is. We have been investigating the role of thymic B cells in negative selection using a system derived from the K/BxN mouse model of inflammatory arthritis, in which both transgene-encoded T cell receptor (TCR) and BCR are specific for the same glucose-6-phosphate isomerase (GPI) self-antigen. Based on our preliminary results, we hypothesize that thymic B cells are efficient APCs in mediating negative selection of T cells for antigens that are recognized by their BCRs and as such contribute to shaping the T cell repertoire. Given the high prevalence of auto- and polyreactive B cell specificities in the immature B cell repertoire, it is likely that B cells within the thymus are capable of presenting a broad range of self-antigens to developing thymocytes. Thus B cell-mediated antigen presentation could represent a novel pathway for negative selection and maintaining T cell tolerance. The insights obtained on the mechanisms of this process may help develop effective antigen- specific therapy for autoimmune diseases. We will pursue the following specific aims: 1) Determine the capacity of antigen-specific thymic B cells in T cell negative selection; 2) Determine the role of thymic B cells in shaping the T cell repertoire; and 3) Determine the contribution of antigen-specific B cells in inducing central versus peripheral T cell tolerance.

描述（由申请人提供）：负选择是中央耐受性的主要机制，从曲目中清除自动反应性T细胞。该过程取决于将自肽呈现为抗原呈递细胞（APC）发育的胸腺细胞。尽管已广泛研究了APC负责负选择的问题，但胸腺B细胞作为APC在阴性选择中的作用已在很大程度上被忽略了。在包括树突状细胞（DC），B细胞和巨噬细胞在内的骨髓衍生的APC中，DC被归因于基于在这些不同细胞种群中比较抗原表现效率的体外测定法中介导负选择。然而，尽管通过非特异性摄取来表现抗原时，B细胞可以呈现抗原与其B细胞受体（BCR）结合的效率甚至比DC更高的抗原。我们的初步研究表明，抗原特异性胸腺B细胞是T细胞阴性选择的极好的APC。 尽管胸腺中B细胞的存在已被识别数十年，但其功能尚未得到很好的了解。它们集中在髓质和皮质中的交界处，以及DCS，并表达高水平的MHC II类。胸腺B细胞删除胸腺细胞的能力已在超抗原模型中证明。目前尚不清楚他们是否可以介导BCR识别的同源抗原的负选择以及它们对T细胞库的影响是什么。我们一直在使用源自炎症性关节炎的K/BXN小鼠模型的系统来研究胸腺B细胞在阴性选择中的作用，其中转基因编码的T细胞受体（TCR）和BCR均针对同一葡萄糖-6-磷酸异构酶（GPI）自抗原。根据我们的初步结果，我们假设胸腺B细胞是有效的APC，可以在介导其BCR识别的T细胞的阴性选择中，这有助于塑造T细胞库。鉴于未成熟的B细胞库中自动和多反应性B细胞特异性的高患病率，胸腺内的B细胞很可能能够表现出广泛的自我抗原剂来发展胸腺细胞。因此，B细胞介导的抗原表现可以代表负选择和维持T细胞耐受性的新途径。对此过程机制获得的见解可能有助于开发自身免疫性疾病的有效抗原疗法。我们将追求以下特定目的：1）确定在T细胞阴性选择中抗原特异性胸腺B细胞的能力； 2）确定胸腺B细胞在塑造T细胞库中的作用； 3）确定抗原特异性B细胞在诱导中心和周围T细胞耐受性方面的贡献。